JP5082382B2 - Process for producing 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one - Google Patents

Description

  The present invention relates to a method for producing 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one useful as various chemical raw materials, intermediates for pharmaceuticals and agricultural chemicals, and the like.

6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one is a useful compound as a raw material for various chemicals, an intermediate for medical and agricultural chemicals, and the like. (For example, refer to Patent Document 1.)
As a method for producing such 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one, there is a method through 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid or an ester thereof. Are known. For example, a method of reacting methyl 4,5-epoxy-3,3-dimethylpentanoate with lithium hexamethyldisilazane (see, for example, Non-Patent Document 1), 2-acetoxymethyl-3,3-dimethylcyclopropane A method of reacting ethyl carboxylate with sodium ethylate (for example, see Patent Document 2), a method of treating 3-halomethyl-2,2-dimethylcyclopropanecarboxylic acid ester with an alkali (for example, see Patent Document 3). Etc.

  However, in the methods of Non-Patent Document 1 and Patent Document 2, 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one that is the target product and 3-hydroxymethyl that is a by-product. -2,2-Dimethylcyclopropanecarboxylic acid ester is not easily separated from the trans isomer, and the method of Patent Document 3 has problems in that it takes several days as a reaction time. This method was not always satisfactory industrially.

Heterocycles, 23, 2589 (1985) JP 61-183239 A JP 56-87533 A JP-A-6-145163

  Under such circumstances, the present inventors obtained 6,6-dimethyl-3-oxabicyclo [3.1.0] via 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid or its ester. As a result of intensive studies on a method for industrially producing hexane-2-one, 3-acyloxymethyl-2,2-dimethylcyclopropanecarboxylic acid ester was subjected to a hydrolysis reaction, and the resulting reaction mixture was subjected to hydrolysis reaction. It has been found that 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one can be produced by subjecting it to a post treatment including a treatment for separating the organic layer and the aqueous layer. The present invention has been reached.

（式中、Ｒ^１はアルキル基を表し、Ｒ^２はアルキル基もしくはハロアルキル基またはアルキル基で置換されていてもよいアリール基を表す。Ｒ^２がアルキル基の場合、Ｒ^１とＲ^２は互いに同一であっても相異なっていてもよい。）
で示されるシクロプロパン化合物をアルカリ加水分解反応後、酸処理する反応に付した後に、水層を除去する６，６−ジメチル−３−オキサビシクロ［３．１．０］ヘキサン−２−オンの製造法を提供するものである。 That is, the present invention provides the formula (1)

(In the formula, R ¹ represents an alkyl group, R ² represents an alkyl group, a haloalkyl group, or an aryl group optionally substituted with an alkyl group. When R ² is an alkyl group, R ¹ and R ² are They may be the same or different.)
The aqueous solution is removed after subjecting the cyclopropane compound represented by formula (1) to an acid treatment after an alkali hydrolysis reaction, and then removing the aqueous layer of 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one. Ru der intended to provide a production method.

  According to the present invention, 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one can be obtained with high yield, and separation from by-products can be performed by simple post-treatment. Is industrially advantageous.

  Hereinafter, the present invention will be described in detail.

  First, the cyclopropane compound represented by formula (1) (hereinafter abbreviated as cyclopropane compound (1)) will be described.

In the formula (1), examples of the alkyl group represented by R ¹ and R ² include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. And a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms such as a group, n-hexyl group, n-octyl group, cyclohexyl group and menthyl group.

Examples of the haloalkyl group represented by R ² include a chloromethyl group and a trichloromethyl group. As an aryl group, C6-C10 aryl groups, such as a phenyl group and a naphthyl group, are mentioned, for example. These aryl groups may be substituted with the alkyl group described above, and examples of the aryl group substituted with the alkyl group include a 2,4,6-trimethylphenyl group.

  Specific examples of the cyclopropane compound (1) include, for example, methyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate, ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate, 3-acetoxymethyl- N-propyl 2,2-dimethylcyclopropanecarboxylate, isopropyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate, n-butyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate, 3-acetoxy Tert-butyl methyl-2,2-dimethylcyclopropanecarboxylate, menthyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate, methyl 3-propionyloxymethyl-2,2-dimethylcyclopropanecarboxylate, 3- Propionyloki Ethyl methyl-2,2-dimethylcyclopropanecarboxylate, 3-propionyloxymethyl-2,2-dimethylcyclopropanecarboxylate n-propyl, isopropyl 3-propionyloxymethyl-2,2-dimethylcyclopropanecarboxylate, 3 -N-butyl propionyloxymethyl-2,2-dimethylcyclopropanecarboxylate, tert-butyl 3-propionyloxymethyl-2,2-dimethylcyclopropanecarboxylate, 3-propionyloxymethyl-2,2-dimethylcyclopropane Menthyl carboxylate, methyl 3-pivaloxymethyl-2,2-dimethylcyclopropanecarboxylate, ethyl 3-pivaloxymethyl-2,2-dimethylcyclopropanecarboxylate, 3-pivaloxymethyl-2,2-dimethylcycloprop N-propyl carboxylate, isopropyl 3-pivaloxymethyl-2,2-dimethylcyclopropanecarboxylate, n-butyl 3-pivaloxymethyl-2,2-dimethylcyclopropanecarboxylate, 3-pivaloxymethyl-2,2-dimethylcyclopropanecarboxylic acid Acid tert-butyl, 3-pivaloxymethyl-2,2-dimethylcyclopropanecarboxylate menthyl, 3-benzoyloxymethyl-2,2-dimethylcyclopropanecarboxylate methyl, 3-benzoyloxymethyl-2,2-dimethylcyclopropane Ethyl carboxylate, n-propyl 3-benzoyloxymethyl-2,2-dimethylcyclopropanecarboxylate, isopropyl 3-benzoyloxymethyl-2,2-dimethylcyclopropanecarboxylate, 3-benzoyloxymethyl N-Butyl-2,2-dimethylcyclopropanecarboxylate, tert-butyl 3-benzoyloxymethyl-2,2-dimethylcyclopropanecarboxylate and menthyl 3-benzoyloxymethyl-2,2-dimethylcyclopropanecarboxylate Etc.

（式中、Ｒ^１は上記と同一の意味を表す。）
で示されるジアゾ酢酸エステルと、式（３）

（式中、Ｒ^２は上記と同一の意味を表す。）
で示されるオレフィン化合物とを、金属触媒の存在下に反応させる方法等が挙げられる。 The production method of the cyclopropane compound (1) is not particularly limited, and for example, the formula (2)

(In the formula, R ¹ represents the same meaning as described above.)
A diazoacetic acid ester represented by the formula (3)

(Wherein R ² represents the same meaning as described above.)
And a method of reacting an olefin compound represented by the above in the presence of a metal catalyst.

  Examples of the diazoacetate ester represented by the above formula (2) (hereinafter abbreviated as diazoacetate ester (2)) include, for example, methyl diazoacetate, ethyl diazoacetate, n-propyl diazoacetate, isopropyl diazoacetate, and diazoacetate n. -Butyl, isobutyl diazoacetate, sec-butyl diazoacetate, tert-butyl diazoacetate, n-hexyl diazoacetate, n-octyl diazoacetate, cyclohexyl diazoacetate, menthyl diazoacetate and the like.

  The diazoacetate ester (2) can be produced, for example, by reacting the corresponding aminoacetate ester with a diazotizing agent such as sodium nitrite.

  Examples of the olefin compound represented by the above formula (3) (hereinafter abbreviated as olefin (3)) include 1-acetoxy-3-methyl-2-butene and 1-propionyloxy-3-methyl-2-butene. 1-butyryloxy-3-methyl-2-butene, 1-pivaloxy-3-methyl-2-butene, 1-chloroacetoxy-3-methyl-2-butene, 1-trichloroacetoxy-3-methyl-2-butene 1-benzoyloxy-3-methyl-2-butene and the like.

  Olefin (3) can be produced by reacting 3-methyl-2-buten-1-ol with the corresponding carboxylic acid halide or the corresponding carboxylic anhydride in the presence of a base. Moreover, you may use a commercial item.

As a metal catalyst,
A group 8 metal of the periodic table or a compound containing the metal element;
A group 9 metal of the periodic table or a compound containing the metal element;
A group 10 metal of the periodic table or a compound containing the metal element;
Compounds containing molybdenum metal or elemental molybdenum;
A compound containing copper metal or copper element;
At least one metal or compound selected from the group consisting of (hereinafter sometimes abbreviated as metal or compound) can be used.

  Examples of the Group 8 metal of the periodic table include iron and ruthenium, examples of the Group 9 metal include cobalt and rhodium, and examples of the Group 10 metal include nickel and palladium.

  Examples of the compound containing each metal element include inorganic metal compounds and organometallic compounds. Examples of the inorganic metal compound include halides, carbonates, hydroxides, oxides, phosphates, sulfates, nitrates, and carbon monoxides of the above metals. Examples of the organometallic compound include cyanides of the above metals; acetate, propionate, 2-ethylhexanoate, octanoate, stearate, trifluoroacetate, trimethylacetate, triphenyl Acetate, oxalate, tartrate, citrate, benzoate, carboxylate such as N-protected amino acid salt; sulfonate such as trifluoromethanesulfonate, p-toluenesulfonate; acetylacetonate complex , Trifluoroacetylacetonato complexes, hexafluoroacetylacetonato complexes, benzoylacetonato complexes, and other acylacetonato complexes; phthalocyanine complexes, hexadecafluorophthalocyanine complexes, 2,3-naphthalocyanine complexes, and other phthalocyanine complexes; bis (cyclopenta Dienyl) complex, bis (pentamethyl) Cyclopentadienyl) complexes, cyclopentadienyl complexes such as bis (diphenylphosphino cyclopentadienyl) complexes; and the like.

  A commercially available metal or compound may be used, or may be produced and used by any known method.

A complex obtained by reacting the above metal or compound with a coordination compound can also be used as a metal catalyst. Examples of such coordination compounds include:
1,2-diphenylethylenediamino-N, N′-bissalicylidene, 1,2-diphenylethylenediamino-N, N′-bis (5-tert-butylsalicylidene), 1,2-cyclohexanediamino-N, N Bissardoimine compounds such as' -bis (3,5-di-tert-butylsalicylidene);
2,2′-methylenebis (4-phenyl-2-oxazoline), 2,2′-methylenebis (4-isopropyl-2-oxazoline), 2,2′-methylenebis (4-tert-butyl-2-oxazoline), 2,2′-methylenebis (4-benzyl-2-oxazoline), 2,2′-methylenebis (4-phenyl-5,5-dimethyl-2-oxazoline), 2,2′-isopropylidenebis (4-phenyl) -2-oxazoline), 2,2′-isopropylidenebis (4-isopropyl-2-oxazoline), 2,2′-isopropylidenebis (4-tert-butyl-2-oxazoline), 2,2′-isopropylidene Ridenbis (4-benzyl-2-oxazoline), 2,2′-isopropylidenebis (4-phenyl-5,5-dimethyl-2-oxazoline), Bisoxazoline compounds such as 2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine and 2,6-bis (4-phenyl-2-oxazolin-2-yl) pyridine;
Amide compounds such as 4-isopropyl-2-oxazolidinone, 4-benzyl-2-oxazolidinone, 4-phenyl-2-oxazolidinone, methyl 2-pyrrolidone-5-carboxylate;
Diamine compounds such as 1,2-diphenylethylenediamino-N, N′-bis (2,4,6-trimethylphenylmethyl);
Phosphine compounds such as triphenylphosphine, tricyclohexylphosphine, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl;
And saldoimine compounds described later.

  In order to efficiently achieve the object of the present invention, the cyclopropane compound (1) is preferably rich in cis form. For the purpose of obtaining such a cis-rich cyclopropane compound (1), the metal catalyst is more preferably a rhodium carboxylate such as rhodium acetate, rhodium trifluoroacetate, rhodium trimethylacetate, rhodium triphenylacetate; A copper complex obtained by reacting with a copper compound.

（式中、Ｒ^３およびＲ^４はそれぞれ同一または相異なって、水素原子、ハロゲン原子、ニトロ基、アルキル基、フルオロアルキル基、アルコキシ基、アルコキシカルボニル基、トリアルキルシリル基またはシアノ基を表し、Ｒ^５はアルキル基、アリール基またはアラルキル基を表し、Ｒ^６およびＲ^７はそれぞれ同一または相異なって、水素原子、アルキル基またはアルコキシ基を表す。また、該化合物が光学活性体である場合に＊は不斉中心を表す。）
で示されるサルドイミン化合物（以下、サルドイミン化合物（６）と略記する。）が挙げられる。 As the saldoimine compound, for example, the formula (6)

(Wherein R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group, a fluoroalkyl group, an alkoxy group, an alkoxycarbonyl group, a trialkylsilyl group or a cyano group; R ⁵ represents an alkyl group, an aryl group or an aralkyl group, and R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, an alkyl group or an alkoxy group, and when the compound is an optically active substance * Represents an asymmetric center.)
And a saldoimine compound (hereinafter abbreviated as a saldoimine compound (6)).

Examples of the halogen atom represented by R ³ and R ⁴ include a fluorine atom, a chlorine atom, and a bromine atom. Examples of the alkyl group include alkyl groups having 1 to 4 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. . Examples of the fluoroalkyl group include an alkyl group having 1 to 4 carbon atoms such as a fluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, and a nonafluorobutyl group. And a group in which one or more hydrogen atoms constituting is substituted with a fluorine atom. Examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentyloxy group, and an n-hexyloxy group. , N-octyloxy groups, isooctyloxy groups, n-decyloxy groups and the like, and alkoxy groups having 1 to 10 carbon atoms. Examples of the alkoxycarbonyl group include alkoxycarbonyl groups having 2 to 5 carbon atoms such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, and a tert-butoxycarbonyl group. It is done. The trialkylsilyl group is a silyl group substituted with the same or different three alkyl groups, and examples thereof include a trimethylsilyl group and a tert-butyldimethylsilyl group.

Examples of the alkyl group represented by R ⁵ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. An alkyl group is mentioned. Examples of the aryl group include a phenyl group and a naphthyl group. Examples of the aralkyl group include a benzyl group and a trityl group.

Examples of the alkyl group represented by R ⁶ and R ⁷ include, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, and the like. -4 alkyl groups are mentioned. Examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentyloxy group, and an n-hexyloxy group. , N-octyloxy groups, isooctyloxy groups, n-decyloxy groups and the like, and alkoxy groups having 1 to 10 carbon atoms.

  Examples of the saldoimine compound (6) include N- (5-nitrosalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -1-propanol, N -(5-nitrosalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1-propanol, N- (5-nitrosalicylide) Den) -2-amino-1,1-di (5-tert-butyl-2-n-octyloxyphenyl) -1-propanol, N- (5-nitrosalicylidene) -2-amino-1,1 -Di (5-tert-butyl-2-n-octyloxyphenyl) -3-phenyl-1-propanol,

N-salicylidene-2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -1-propanol, N- (5-fluorosalicylidene) -2-amino-1,1 -Di (5-tert-butyl-2-n-butoxyphenyl) -1-propanol, N- (5-chlorosalicylidene) -2-amino-1,1-di (5-tert-butyl-2- n-butoxyphenyl) -1-propanol, N- (5-methoxycarbonylsalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -1-propanol, N- (5-ethoxycarbonylsalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -1-propanol, N- [5- (n-propoxycarbo) D ) Salicylidene] -2-amino-1,1-di (5-tert-butyl -2-n-butoxy-phenyl) -1-propanol,

N- (5-isopropoxycarbonylsalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -1-propanol, N- (5-fluoromethylsalicylide) Den) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -1-propanol, N- (5-difluoromethylsalicylidene) -2-amino-1,1 -Di (5-tert-butyl-2-n-butoxyphenyl) -1-propanol, N- (5-trifluoromethylsalicylidene) -2-amino-1,1-di (5-tert-butyl- 2-n-butoxyphenyl) -1-propanol,

N-salicylidene-2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1-propanol, N- (5-fluorosalicylidene) -2-amino -1,1-di (5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1-propanol, N- (5-chlorosalicylidene) -2-amino-1,1-di ( 5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1-propanol, N- (5-methoxycarbonylsalicylidene) -2-amino-1,1-di (5-tert-butyl- 2-n-butoxyphenyl) -3-phenyl-1-propanol, N- (5-ethoxycarbonylsalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1-propanol, N- [5- (n-propoxycarbonyl) salicylidene] -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -3-phenyl -1-propanol,

N- (5-isopropoxycarbonylsalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1-propanol, N- (5- Fluoromethylsalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1-propanol, N- (5-difluoromethylsalicylidene) 2-Amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1-propanol, N- (5-trifluoromethylsalicylidene) -2-amino- 1,1-di (5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1-propanol,

N-salicylidene-2-amino-1,1-di (5-tert-butyl-2-n-octyloxyphenyl) -1-propanol, N- (5-fluorosalicylidene) -2-amino-1, 1-di (5-tert-butyl-2-n-octyloxyphenyl) -1-propanol, N- (5-chlorosalicylidene) -2-amino-1,1-di (5-tert-butyl- 2-n-octyloxyphenyl) -1-propanol, N- (5-methoxycarbonylsalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-octyloxyphenyl)- 1-propanol, N- (5-ethoxycarbonylsalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-octyloxyphenyl) -1-propanol, N- 5-(n-propoxycarbonyl) salicylidene] -2-amino-1,1-di (5-tert-butyl -2-n-octyloxy phenyl) -1-propanol,

N- (5-isopropoxycarbonylsalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-octyloxyphenyl) -1-propanol, N- (5-fluoromethylsalicyclic) Tylidene) -2-amino-1,1-di (5-tert-butyl-2-n-octyloxyphenyl) -1-propanol, N- (5-difluoromethylsalicylidene) -2-amino-1 , 1-di (5-tert-butyl-2-n-octyloxyphenyl) -1-propanol, N- (5-trifluoromethylsalicylidene) -2-amino-1,1-di (5-tert -Butyl-2-n-octyloxyphenyl) -1-propanol,

N-salicylidene-2-amino-1,1-di (5-tert-butyl-2-n-octyloxyphenyl) -3-phenyl-1-propanol, N- (5-fluorosalicylidene) -2- Amino-1,1-di (5-tert-butyl-2-n-octyloxyphenyl) -3-phenyl-1-propanol, N- (5-chlorosalicylidene) -2-amino-1,1- Di (5-tert-butyl-2-n-octyloxyphenyl) -3-phenyl-1-propanol, N- (5-methoxycarbonylsalicylidene) -2-amino-1,1-di (5-tert -Butyl-2-n-octyloxyphenyl) -3-phenyl-1-propanol, N- (5-ethoxycarbonylsalicylidene) -2-amino-1,1-di (5-tert-butyl- -N-octyloxyphenyl) -3-phenyl-1-propanol, N- [5- (n-propoxycarbonyl) salicylidene] -2-amino-1,1-di (5-tert-butyl-2-n- Octyloxyphenyl) -3-phenyl-1-propanol,

N- (5-isopropoxycarbonylsalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-octyloxyphenyl) -3-phenyl-1-propanol, N- (5 -Fluoromethylsalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-octyloxyphenyl) -3-phenyl-1-propanol, N- (5-difluoromethylsalicylide) Den) -2-amino-1,1-di (5-tert-butyl-2-n-octyloxyphenyl) -3-phenyl-1-propanol, N- (5-trifluoromethylsalicylidene) -2 -Amino-1,1-di (5-tert-butyl-2-n-octyloxyphenyl) -3-phenyl-1-propanol,

N- (6-trimethylsilylsalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -1-propanol, N- (6-tert-butyldimethylsilylsali) Tylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -1-propanol, N- (6-trimethylsilylsalicylidene) -2-amino-1,1 -Di (5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1-propanol, N- (6-tert-butyldimethylsilylsalicylidene) -2-amino-1,1-di ( 5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1-propanol,

N- (6-trimethylsilylsalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-octyloxyphenyl) -1-propanol, N- (6-tert-butyldimethylsilyl) Salicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-octyloxyphenyl) -1-propanol, N- (6-trimethylsilylsalicylidene) -2-amino-1 , 1-Di (5-tert-butyl-2-n-octyloxyphenyl) -3-phenyl-1-propanol, N- (6-tert-butyldimethylsilylsalicylidene) -2-amino-1,1 -Di (5-tert-butyl-2-n-octyloxyphenyl) -3-phenyl-1-propanol,

N- (3-fluorosalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1-propanol, N- (3-chlorosali Tylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1-propanol, N-salicylidene-2-amino-1,1-diphenyl- 1-propanol, N- (3-methoxy-5-nitrosalicylidene) -2-amino-1,1-diphenyl-1-propanol, N- (3,5-dinitrosalicylidene) -2-amino- 1,1-diphenyl-1-propanol, N- (5-nitrosalicylidene) -2-amino-1,1-di (2-methoxyphenyl) -1-propanol, N- (3,5-dichlorosali Chilidene)- -Amino-1,1-di (2-methoxyphenyl) -1-propanol, N- (5-nitrosalicylidene) -2-amino-1,1-di (2-methoxyphenyl) -3-methyl- 1-butanol, N- (3,5-di-tert-butylsalicylidene) -2-amino-1,1-di (2-methoxyphenyl) -1-propanol and the like can be mentioned.

  As the saldoimine compound (6), either a racemate or an optically active substance may be used. When it is desired to obtain 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one as an optically active substance, it is preferable to use an optically active substance for the saldoimine compound (6). The optically active saldoimine compound (6) has two optical isomers, R-form and S-form, any of which may be used in the present invention, and the desired optically active 6,6-dimethyl-3- What is necessary is just to select suitably according to oxabicyclo [3.1.0] hexane-2-one.

Saludoimine compound (6) is described in, for example, Tetrahedron Lett. , 16 , 1707 (1975), Japanese Patent Application Laid-Open No. 2001-278853, and the like.

  As the copper compound to be reacted with the saludoimine compound (6), a monovalent or divalent copper compound is used. For example, copper acetate (I), copper acetate (II), copper naphthenate (I), copper naphthenate (II ), Copper carboxylic acid having 2 to 15 carbon atoms such as copper (I) octylate, copper (II) octylate, such as copper (I) chloride, copper (II) chloride, copper (I) bromide, copper bromide Copper halides such as (II), copper nitrate (I), copper nitrate (II), such as copper (I) methanesulfonate, copper (II) methanesulfonate, copper (I) trifluoromethanesulfonate, trifluoromethanesulfone Examples thereof include copper sulfonates such as acid copper (II). Such copper compounds may be used alone or in combination. These copper compounds may be anhydrides or hydrates.

  Preparation of the copper complex by reaction of a saludoimine compound (6) and a copper compound can be implemented according to the method as described in Unexamined-Japanese-Patent No. 2001-278853 etc., for example.

  Next, the reaction of diazoacetic acid ester (2) and olefin (3) in the presence of a metal catalyst (hereinafter sometimes referred to as cyclopropanation reaction) will be described.

  The amount of the olefin (3) used is usually 1 mole or more with respect to the diazoacetate ester (2), and there is no particular upper limit. When the olefin (3) is liquid under the reaction conditions, A large excess of 3) may be used as a solvent.

  The usage-amount of a metal catalyst is 0.01-10 mol% normally in metal conversion with respect to diazoacetate ester (2).

  The cyclopropanation reaction is usually carried out by contacting and mixing the metal catalyst, diazoacetic acid ester (2) and olefin (3), and the mixing order is not particularly limited. For example, the metal catalyst and olefin (3) are mixed. The diazoacetate ester (2) may be added to the mixture, and the olefin (3) and diazoacetate ester (2) may be added to the metal catalyst. The olefin (3) and diazoacetic acid ester (2) may be added continuously or intermittently. The cyclopropanation reaction may be performed under normal pressure conditions or under pressurized conditions. The reaction temperature is usually in the range of −20 ° C. to 150 ° C., preferably −10 to 100 ° C.

  In order to make the reaction proceed more smoothly, for example, a reducing agent such as phenylhydrazine may coexist. When a copper complex obtained by reacting the saldoimine compound (6) with a copper compound is used as the metal catalyst, such a reducing agent may be added at the time of preparing the complex. The amount of the reducing agent used is usually in the range of 0.1 to 3 mole times, preferably 0.9 to 1.2 mole times with respect to the metal catalyst.

  This reaction is usually carried out in the presence of a solvent. Examples of the solvent include aliphatic hydrocarbon solvents such as hexane, heptane and cyclohexane; aromatic hydrocarbon solvents such as toluene, xylene, monochlorobenzene and dichlorobenzene; tetrahydrofuran Ether solvents such as methyl-tert-butyl ether, 1,2-dimethoxyethane and 1,4-dioxane; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chlorobutane; ester solvents such as methyl acetate, ethyl acetate and butyl acetate; The amount used is not particularly limited, but in consideration of economic efficiency, volumetric efficiency, etc., it is practically 100 weight times or less with respect to the diazoacetic acid ester (2). Further, as described above, when the olefin (3) is liquid under the reaction conditions, the olefin (3) may be used as a solvent.

  After completion of the reaction, a mixture containing the cyclopropane compound (1) is obtained by removing insolubles by performing filtration treatment, washing treatment, or the like as necessary. For the hydrolysis reaction of the cyclopropane compound (1), the mixture may be used as it is, or the cyclopropane compound (1) isolated by subjecting it to usual post-treatment such as distillation, column chromatography, etc. You may use for a decomposition reaction.

  Next, the hydrolysis reaction of the cyclopropane compound (1) will be described.

  The hydrolysis reaction in the present invention is not particularly limited as long as the two ester bonds of the cyclopropane compound (1) can be hydrolyzed together. Even if it is an alkaline hydrolysis reaction, the acid hydrolysis reaction is not limited. It may be. Moreover, the hydrolysis reaction implemented using an enzyme etc. on neutral conditions may be sufficient. Preferably, it is an alkali hydrolysis reaction.

  Examples of the base used in the alkali hydrolysis reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; And alkali metal carbonates such as lithium, sodium carbonate and potassium carbonate. Preferably, an alkali metal hydroxide is used.

  The usage-amount of a base is 2-20 mol times normally with respect to a cyclopropane compound (1), Preferably it is the range of 3-10 mol times.

  Examples of the acid used for the acid hydrolysis reaction include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid; organic acids such as trifluoroacetic acid and methanesulfonic acid; and the like.

  The usage-amount of an acid is 2-20 mol times normally with respect to a cyclopropane compound (1), Preferably it is the range of 3-10 mol times.

  The enzyme used for the enzymatic hydrolysis reaction is not particularly limited as long as it has an ability to hydrolyze the ester bond of the cyclopropane compound (1). For example, ester hydrolysis of lipase, esterase, etc. Enzymes. These may be commercially available products, or the microorganisms or the processed products of the enzyme may be used.

  The hydrolysis reaction is carried out by stirring and mixing the base, acid or enzyme and the cyclopropane compound (1) in water or a mixed solvent of water and an organic solvent.

  Examples of the organic solvent include alcohol solvents such as methanol, ethanol and 2-propanol; aliphatic hydrocarbon solvents such as hexane, heptane and cyclohexane; aromatic hydrocarbon solvents such as toluene, xylene, monochlorobenzene and dichlorobenzene; tetrahydrofuran Ether solvents such as methyl, tert-butyl ether, 1,2-dimethoxyethane and 1,4-dioxane; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chlorobutane; ketone solvents such as acetone and methyl isobutyl ketone; acetonitrile, propio Nitrile solvents such as nitrile; amide solvents such as N, N′-dimethylformamide, N, N′-dimethylacetamide, N-methylpyrrolidinone; ester solvents such as methyl acetate, ethyl acetate, butyl acetate; and And mixtures thereof.

  The usage-amount of water is 0.5-100 weight times normally with respect to a cyclopropane compound (1), Preferably it is the range of 1-20 weight times. The usage-amount of an organic solvent is 0-50 weight times normally with respect to a cyclopropane compound (1), Preferably it is the range of 0-10 weight times.

  The reaction temperature is usually in the range of 0 to 150 ° C, preferably 10 to 100 ° C. The progress of the reaction can be confirmed by ordinary analytical means such as gas chromatography, high performance liquid chromatography, thin layer chromatography, NMR, IR and the like.

  By subjecting the reaction mixture obtained after the hydrolysis reaction to a post-treatment including a treatment for separating the organic layer and the aqueous layer, 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2 -ON can be selectively extracted. Hereinafter, such post-processing will be described.

  The post-treatment of the present invention may be any treatment that separates the organic layer and the aqueous layer once or more, and in addition to the usual post-treatment such as filtration, extraction, washing, and concentration. Processing may be included.

  When the hydrolysis reaction is acid hydrolysis or enzymatic hydrolysis, the reaction mixture is usually separated into two layers of an organic layer and an aqueous layer, and 6,6-dimethyl-3-oxabicyclo [3. 1.0] Hexane-2-one is present. If this is mixed as it is, or if necessary with water and / or an organic solvent incompatible with water and then the organic layer and the aqueous layer are separated, 6,6-dimethyl-3-oxabicyclo is obtained as the organic layer. [3.1.0] Hexan-2-one can be removed.

  When the hydrolysis reaction is an alkaline hydrolysis reaction, the main product is usually present in the aqueous layer as a salt of 3-hydroxymethyl-2,2-cyclopropanecarboxylic acid. When the reaction mixture after the hydrolysis reaction is treated with acid, a cis isomer of 3-hydroxymethyl-2,2-cyclopropanecarboxylic acid is cyclized intramolecularly to give 6,6-dimethyl-3-oxabicyclo [3.1. .0] Hexane-2-one is formed. The progress of the reaction can be confirmed by ordinary analytical means such as gas chromatography, high performance liquid chromatography, thin layer chromatography, NMR, IR and the like. As such acid treatment, for example, a reaction mixture after hydrolysis, an acid and, if necessary, water are mixed, or an aqueous layer separated from the reaction mixture after hydrolysis reaction, an acid, and if necessary The process etc. which mix the water and / or the organic solvent incompatible with water are mentioned. Preferably, it is the process which mixes the water layer fractionated from the reaction mixture after a hydrolysis reaction, an acid, and if necessary water and / or an organic solvent incompatible with water. The pH during the acid treatment is usually 6 or less, preferably 0 to 5. Examples of the acid used for the acid treatment include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid and phosphoric acid; organic acids such as acetic acid, citric acid and methanesulfonic acid. An inorganic acid is preferable.

  The mixture obtained by the acid treatment after the alkalized water splitting reaction is usually separated into two layers of an organic layer and an aqueous layer, and 6,6-dimethyl-3-oxabicyclo [3.1.0] is separated into the organic layer. Hexan-2-one is present. If this is mixed as it is, or if necessary with water and / or an organic solvent incompatible with water and then the organic layer and the aqueous layer are separated, 6,6-dimethyl-3-oxabicyclo is obtained as the organic layer. [3.1.0] Hexan-2-one can be removed.

  In the treatment for separating the organic layer and the aqueous layer in order to take out 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one as described above, if the pH of the aqueous layer is too high, 6-Dimethyl-3-oxabicyclo [3.1.0] hexane-2-one may hydrolyze. If it is too low, the organic layer contains a large amount of 3-hydroxymethyl-2,2-cyclopropanecarboxylic acid. There is a risk of being. Accordingly, the pH of the aqueous layer during the treatment is usually in the range of 0 to 10, preferably 6 to 8. An acid or a base can be appropriately used for adjusting the pH.

  Examples of the acid used for the pH adjustment include those exemplified as the acid used for the acid treatment. Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkalis such as sodium carbonate and potassium carbonate Metal carbonates; alkaline earth metal carbonates such as calcium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; triethylamine And organic bases such as pyridine; ammonia; and the like. Preferably, it is an alkali metal hydroxide.

  Examples of the organic solvent incompatible with water include aliphatic hydrocarbon solvents such as hexane, heptane, and cyclohexane; aromatic hydrocarbon solvents such as toluene, xylene, monochlorobenzene, and dichlorobenzene; methyl-tert-butyl ether, 1 Ether solvents such as 1,2-dimethoxyethane; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chlorobutane; ketone solvents such as methyl isobutyl ketone; ester solvents such as methyl acetate, ethyl acetate and butyl acetate; An aromatic hydrocarbon solvent is preferable, and toluene is more preferable. These solvents may be used as a mixture of two or more.

  The temperature during the post-treatment is usually in the range of 0 to 100 ° C, preferably 10 to 50 ° C.

  By subjecting the organic layer containing 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one obtained by the above-mentioned post-treatment to normal isolation treatment such as concentration, 6-Dimethyl-3-oxabicyclo [3.1.0] hexane-2-one can be isolated.

  In addition to 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one, 3-hydroxymethyl-2,2-cyclopropanecarboxylic acid as an impurity was added to the treated product after the isolation treatment. If included, 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one can be purified by distillation. The distillation treatment may of course be carried out by rectification, but can be sufficiently purified by simple distillation which can be carried out industrially more simply. Although the pressure at the time of a distillation process is not specifically limited, Usually, it is the range of 0.01-20 KPa. Although distillation temperature changes with the said pressure conditions, it is the range of 50-300 degreeC normally.

  Moreover, it is also possible to perform the said distillation process in presence of a solvent whose boiling point is higher than 6, 6- dimethyl- 3-oxabicyclo [3.1.0] hexane-2-one. By performing the distillation operation in the presence of such a solvent, it becomes possible to improve the recovery rate of 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one, which is industrially advantageous. It is. The solvent used for this purpose is not particularly limited as long as it has a boiling point higher than that of 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one. For example, liquid paraffin, Mineral oil, higher fatty acids, higher fatty acid esters and the like can be mentioned. Specific examples include di (2-ethylhexyl) phthalate.

  When a racemate is used as the cyclopropane compound (1), racemic 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one is usually obtained, and the cyclopropane compound (1) is obtained. If an optically active substance is used, optically active 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one is usually obtained.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by these examples.

Example 1
Synthesis of ethyl (1R, 3S) -cis-3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate:
Copper (II) acetate and (S) -N- (5-nitrosalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -1-propanol A copper complex (0.834 kg, 1.20 mol) and 1-acetoxy-3-methyl-2-butene (30.8 kg, 240 mol) were dissolved in 47.2 kg of ethyl acetate and adjusted to 10 ° C. Hydrazine (0.16 kg, 1.45 mol) was added and stirred for 0.5 hour. To this solution, 35.0 kg of a toluene solution containing 13.7 kg (120 mol) of ethyl diazoacetate was added dropwise at the same temperature over 9 hours, and kept at the same temperature for 2 hours. To this solution, 21.9 kg of an aqueous solution containing 0.5 mol of ethylenediaminetetraacetic acid-3 sodium salt per liter was added, mixed and separated, and 11.0 kg of water was further added to the organic layer and mixed and separated. After the solvent in the obtained organic layer was distilled off under reduced pressure, a solution 30 containing 19.3 kg of ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate (yield 75.0% based on ethyl diazoacetate) 30 .5 kg was obtained. The cis / trans isomer ratio was 83.4 / 16.6, and the optical purity of the (1R) -cis isomer was 93.4% ee.

  The quantitative and cis / trans ratio of ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate was determined by gas chromatography. The column used was DB-WAX (0.25 μm), 0.25 mmφ × 30 m manufactured by J & J.

  On the other hand, the optical purity was determined by high performance liquid chromatography. As the column, CHIRALCEL OJ-R manufactured by Daicel Corporation, 4.6 mmφ × 15 cm (two) was used.

The boiling point and ¹ H-NMR results (using CDCl ₃ ) of ethyl (1R, 3S) -3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate are shown below.

Boiling point: 112-116 ° C. (1.0 KPa)
: Δ = 4.49dd (2H), 4.40dd (2H), 4.11q (2H), 2.05s (3H), 1.59d (1H), 1.44dt (1H), 1.27s (3H) ), 1.26t (3H), 1.20s (3H)

Example 2
Synthesis of ethyl (1S, 3R) -cis-3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate:
Copper (II) acetate and (R) -N- (5-nitrosalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1 30 mg (0.039 mmol) of a copper complex obtained by reacting with -propanol was dissolved in 1.2 g of ethyl acetate, and a solution consisting of 0.0044 mg (0.041 mmol) of phenylhydrazine and 4.5 g of ethyl acetate was added. This solution was adjusted to 20 ° C., and a solution consisting of 0.46 g (4.03 mmol) of ethyl diazoacetate and 5.15 g (40.2 mmol) of 1-acetoxy-3-methyl-2-butene was added dropwise over 2 hours. . After maintaining at the same temperature for 0.5 hours, the solvent was distilled off, and then a solution containing 0.46 g of ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate (yield 53% based on ethyl diazoacetate) was obtained. It was. The cis / trans isomer ratio was 77/23, and the optical purity of the (1S) -cis isomer was 86% ee.

Example 3
Synthesis of ethyl (1S, 3R) -cis-3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate:
Instead of the copper complex of Example 2, copper (II) acetate and (R) -N- (5-nitrosalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n -Butoxyphenyl) ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate in the same manner as in Example 2 except that 27 mg (0.039 mmol) of a copper complex obtained by reacting with 1-propanol was used. A solution containing 0.59 g (68% yield based on ethyl diazoacetate) was obtained. The cis / trans isomer ratio was 75/25, and the optical purity of the (1S) -cis isomer was 91% ee.

Example 4
Synthesis of ethyl racemic-cis-3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate:
6.78 mg (0.01 mmol) of rhodium triphenylacetate was dissolved in 9.0 g of ethyl acetate, 2.56 g (20.0 mmol) of 1-acetoxy-3-methyl-2-butene was added, and the temperature was raised to 50 ° C. Warm up. A solution consisting of 1.14 g (10.0 mmol) of ethyl diazoacetate and 3.6 g of ethyl acetate was added dropwise to this solution over 2 hours, and the mixture was kept at the same temperature for 0.5 hour. An aqueous solution containing 0.5 mol of ethylenediaminetetraacetic acid-3sodium salt per liter was added to this solution, mixed and separated, and 1.82 g of ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate (ethyl diazoacetate). To give a solution with a yield of 84.8%). The cis / trans ratio was 72/28.

Example 5
Synthesis of (1R, 5S) -6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one:
8.53 kg of ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate obtained in Example 1 (39.8 mol, cis / trans ratio was 83.4 / 16.6, (1R) -cis The optical purity of the body was 93.5% ee), 9.1 kg of water was added to 9.1 kg of water, the temperature was raised to 50 ° C., and 24.2 kg of 28% aqueous sodium hydroxide solution was added dropwise over 4 hours. And kept warm for 2 hours. After confirming that ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate had disappeared and was converted to 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid, 25.6 kg of toluene was added to this solution. Were added, mixed and separated to remove the organic layer. Further, 17.1 kg of toluene was added to the aqueous layer, mixed and separated, and the organic layer was similarly removed. To the obtained aqueous layer, 21.8 kg of 35% hydrochloric acid was added at 20 ° C. and kept warm for 3 hours. After confirming that cis-3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid was converted to 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one, 28 % Aqueous sodium hydroxide solution was added dropwise to adjust the pH of the solution to 7. This solution was extracted three times with 17.1 kg of toluene, and the resulting three toluene solutions were combined to give 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2- 55.7 kg of toluene solution containing 4.05 kg of ON (32.1 mol, yield 96.7% with respect to ethyl cis-3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate) was obtained. In this toluene solution, trans-3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid was not detected.

Example 7
Synthesis of (1R, 5S) -6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one:
Ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate 512.1 g (2.39 mol, cis / trans ratio is 80.3 / 19.7, optical purity of (1R) -cis is 93. After 747 g of a solution containing 3% ee) was heated to 50 ° C., 1975 g of 20% aqueous sodium hydroxide solution was added dropwise, and the mixture was kept at the same temperature for 10 hours. To this solution was added 1536 g of toluene, mixed and separated to remove the organic layer.
Further, 1024 g of toluene was added to the aqueous layer, mixed and separated to remove the organic layer. To the obtained aqueous layer, 1277 g of 35% hydrochloric acid was added and kept at 50 ° C. for 1 hour.

  The following cis body / trans body separation operation was performed using 20.1 g of the obtained solution 4041 g. A 20% aqueous sodium hydroxide solution was added dropwise to 20.1 g of this solution to adjust the pH of the solution to 3. From this solution, extraction operation was performed 3 times using 7.8 g of toluene, and the obtained organic layers were combined. Subsequently, after toluene was distilled off, 1.17 g (9.27 mmol, cis-3-acetoxymethyl-2,2-dimethyl) of 6,6-dimethyl-3-oxabicyclo [3.1.0] hexan-2-one 1.49 g of a solution containing 97.2% yield with respect to ethyl cyclopropanecarboxylate and (1R, 5S) -form optical purity of 92.8% ee) was obtained. In this toluene solution, 0.057 g (0.39 mmol) of trans-3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid was present.

  This solution was further distilled in the same manner as in Example 6 to completely transfer trans-3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid and 6,6-dimethyl-3-oxabicyclo [3.1.0. It was possible to separate and purify hexane-2-one.

Example 8
Synthesis of (1R, 5S) -6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one:
Except that the pH during extraction of 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one of Example 7 with toluene was set to 1, -1.20 g of dimethyl-3-oxabicyclo [3.1.0] hexane-2-one (9.49 mmol, yield 99.4 based on ethyl cis-3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate) %, (1R, 5S) -form optical purity 92.8% ee) was obtained. In this toluene solution, 0.062 g (0.43 mmol) of trans-3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid was present.

  This solution was further distilled in the same manner as in Example 6 to obtain trans-3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid and 6,6-dimethyl-3-oxabicyclo [3.1.0]. It could be separated into hexane-2-one.

Example 9
Synthesis of ethyl (1R, 3S) -cis-3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate:
Copper (II) acetate and (S) -N- (5-nitrosalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -1-propanol 278 mg (0.40 mmol) of the copper complex to be reacted was dissolved in 15.75 g (122.9 mmol) of 1-acetoxy-3-methyl-2-butene. This solution was adjusted to 10 ° C., a solution consisting of 0.053 g (0.48 mmol) of phenylhydrazine and 0.46 g (3.6 mmol) of 1-acetoxy-3-methyl-2-butene was added, and the same temperature was maintained for 5 minutes. After keeping the temperature, a solution consisting of 4.56 g (40.0 mmol) of ethyl diazoacetate, 5.33 g (41.6 mmol) of 1-acetoxy-3-methyl-2-butene and 3.60 g of toluene was added dropwise over 10 hours. . After 0.5 hours at the same temperature, 8.0 g of an aqueous solution containing 8.0 g of an aqueous solution containing 0.5 mol of ethylenediaminetetraacetic acid-3 sodium salt per liter was added to this solution, mixed and separated. -33.23 g of a solution containing 6.81 g of ethyl acetoxymethyl-2,2-dimethylcyclopropanecarboxylate (yield 79.5% based on ethyl diazoacetate) was obtained. The cis / trans isomer ratio was 83.1 / 16.9, and the optical purity of the (1R) -cis isomer was 90.8% ee.

Claims (12)

Formula (1)

(In the formula, R ¹ represents an alkyl group, R ² represents an alkyl group, a haloalkyl group, or an aryl group optionally substituted with an alkyl group. When R ² is an alkyl group, R ¹ and R ² are They may be the same or different.)
The aqueous solution is removed after subjecting the cyclopropane compound represented by formula (1) to an acid treatment after an alkali hydrolysis reaction, and then removing the aqueous layer of 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one. Manufacturing method. The production method according to claim 1, wherein the alkali hydrolysis reaction is a hydrolysis reaction carried out in the presence of an alkali metal hydroxide. The production method according to claim 1 or 2, wherein the pH of the aqueous layer to be removed is in the range of 0 to 10. The method according to claim 1 or 2, wherein the pH of the aqueous layer to be removed is in the range of 6-8. The production method according to any one of claims 1 to 4, wherein the aqueous layer is removed in the presence of an organic solvent incompatible with water. The production method according to claim 5, wherein the organic solvent incompatible with water is an aromatic hydrocarbon solvent. The production method according to claim 6, wherein the aromatic hydrocarbon solvent is toluene. The cyclopropane compound represented by the formula (1) is represented by the formula (2)

(In the formula, R ¹ represents the same meaning as described above.)
A diazoacetic acid ester represented by the formula (3)

(Wherein R ² represents the same meaning as described above.)
The production method according to any one of claims 1 to 7, which is a cyclopropane compound obtained by reacting the olefin compound represented by formula (1) with a metal catalyst. The process according to claim 8, wherein the metal catalyst is a rhodium carboxylate. The metal catalyst has the formula (6)

(Wherein R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group, a fluoroalkyl group, an alkoxy group, an alkoxycarbonyl group, a trialkylsilyl group or a cyano group; R ⁵ represents an alkyl group, an aryl group or an aralkyl group, and R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, an alkyl group or an alkoxy group, and when the compound is an optically active substance * Represents an asymmetric center.)
The manufacturing method of Claim 8 which is a copper complex formed by making the saldoimine compound and copper compound shown by these react. The saldoimine compound represented by formula (6) is N- (5-nitrosalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -1-propanol or 11. N- (5-nitrosalicylidene) -2-amino-1,1-di (5-tert-butyl-2-n-butoxyphenyl) -3-phenyl-1-propanol. Manufacturing method. The saldoimine compound represented by the formula (6) is an optically active substance, and the obtained 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one is an optically active substance. 10. The production method according to 10 or 11.